WO2020143674A1 - Composés et leur utilisation dans la synthèse de principes actifs pharmaceutiques brivaracétam - Google Patents

Composés et leur utilisation dans la synthèse de principes actifs pharmaceutiques brivaracétam Download PDF

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WO2020143674A1
WO2020143674A1 PCT/CN2020/070948 CN2020070948W WO2020143674A1 WO 2020143674 A1 WO2020143674 A1 WO 2020143674A1 CN 2020070948 W CN2020070948 W CN 2020070948W WO 2020143674 A1 WO2020143674 A1 WO 2020143674A1
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compound
formula
acid
reducing agent
tempo
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PCT/CN2020/070948
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English (en)
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Ruyong WANG
Yizhang YE
Xuan GONG
Fengsen ZHANG
Zhonghong WANG
Dandan Li
Yueli FU
Yan Feng
Xinshan Kang
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Fujian Haixi Pharmaceuticals Co., Ltd
Xinshan Kang
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Priority to CN202080002479.6A priority Critical patent/CN112154140B/zh
Publication of WO2020143674A1 publication Critical patent/WO2020143674A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms

Definitions

  • the invention relates to the field of API synthesis, and in particular to the synthesis of Brivaracetam intermediates and APIs.
  • the information provided is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to be prior art to the present invention. Each of the references cited is incorporated herein in its entirety and for any purpose.
  • Brivaracetam belongs to the third generation antiepileptic drug and is a novel high-affinity ligand for synaptophysin 2A (SV2A) , which also inhibits voltage-dependent sodium channels.
  • SV2A synaptophysin 2A
  • Brivaracetam was approved by the FDA for the treatment of seizures, and the results showed that Brivaracetam has a good effect on generalized seizures.
  • the original patent CN1882535A discloses a preparation method of Brivaracetam, and the synthesis route is as follows:
  • the final product of this synthesis route is the mixture of Brivaracetam and its diastereomer (2S) -2- ( (4S) -2-oxo-4-propyl-1-pyrrolidine) butylamide. It is necessary to use (chiralpak ad 20 ⁇ m) chiral solid phase and n-hexane/ethanol (45/55, V/V) as eluent at 25 ⁇ 2°C to separate the above mixture by chromatography, so as to obtain a high purity Brivaracetam.
  • This method has the disadvantages of low separation efficiency and high production cost, and the second step uses catalytic hydrogenation, which requires higher synthesis equipment.
  • the crude Brivaracetam obtained by this method needs to be separated by a silica gel column before crystal separation to obtain a pure product, and the high-performance liquid chromatography analysis finds that the purity is 83-88%and the impurity content is high.
  • WO2007065634A1 provides another synthetic route for the preparation of Brivaracetam, which requires the use of a relatively expensive metal catalyst RuCl 3 , and the preparation method also uses a chiral column to separate Brivaracetam and its diastereomer
  • CN106365986A provides another synthetic route for the preparation of Brivaracetam.
  • the route is novel, with high chiral purity and low production cost.
  • the UV absorption of the reaction intermediate is relatively weak, which makes it difficult to detect and control the quality.
  • Many intermediates are liquid and need to be used for vacuum distillation, which requires high equipment.
  • the purpose of the present invention is to provide a method for preparing a compound such as formula III, and its use in the synthesis of Brivaracetam APIs. This method achieves creative breakthroughs. It has the advantages of short synthetic routes, easy-to-obtain raw materials, simple process, easy detection and quality control of intermediates, etc. Compared with the existing synthetic technology, it has very obvious cost and process advantages, which is very suitable for the industrial production of Brivaracetam APIs.
  • the present invention provides a compound of formula III, which is applicable to the preparation of Brivaracetam APIs.
  • a compound for the preparation of Brivaracetam has the structure of formula III:
  • R is selected from optionally substituted or unsubstituted C 1 -C 5 alkyl, optionally substituted or unsubstituted C 6 -C 12 Aryl, and optionally susbstituted or unsubstituted 5-12 membered heteroaryl;
  • R 2 is selected from OH, NH 2 , NHBn, NBn 2 or optionally susbstituted or unsubstituted alkoxy;
  • R 3 is selected from hydrogen, OH, optionally substituted or unsubstituted C 1 -C 4 alkoxy, optionally substituted or unsubstituted OC (O) (C 1 -C 4 ) alkyl or OBz.
  • R 1 is selected from an optionally substituted or unsubstituted phenyl group, an optionally substituted or unsubstituted naphthyl group, an optionally substituted or unsubstituted pyridyl or quinolyl group; in further embodiments, R 1 is selected from arbitrarily substituted or unsubstituted phenyl.
  • R 1 is selected from an optionally substituted or unsubstituted phenyl group, an optionally substituted or unsubstituted naphthyl group, an optionally substituted or unsubstituted pyridyl or quinolyl group, and the hydrogen on R 1 may be substituted by one or more R 4 groups, R 4 is selected from halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, nitro, cyano.
  • R 1 is selected from an optionally substituted or unsubstituted phenyl group, the hydrogen on R 1 may be substituted by one or more R 4 groups, and R 4 is selected halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, nitro, cyano.
  • R 1 is selected from:
  • R 2 is selected from OH or NH 2 .
  • R 2 is selected from OH or NH 2 ; R 3 is selected from OH. In some further preferred embodiments, R 2 is selected from NH 2 , and R 3 is selected from OH. In some further preferred embodiments, R 2 and R 3 are selected from OH.
  • R 2 is selected from OH or NH 2 ; R 3 is selected from hydrogen. In some further preferred embodiments, R 2 is selected from NH 2 , and R 3 is selected from hydrogen. In some further preferred embodiments, R 2 is selected from OH and R 3 is selected from hydrogen.
  • the application provides a method for preparing a compound of formula III-1, which method comprises the following steps:
  • R 2 is selected from OH or NH 2 .
  • the application provides a method for preparing a compound of formula III-2, which method comprises the following steps:
  • R 2 is selected from OH or NH 2 .
  • reaction conditions of each reaction step may be:
  • the compound of formula II is prepared by reacting a compound of formula I with compound A in a solvent or solvent free condition.
  • the aforementioned compound A includes L-2-aminobutanamide, L-2-aminobutanamide hydrochloride, L-2-aminobutyric acid or L-2-aminobutyric acid hydrochloride.
  • the compound of formula I is reacted with compound A under the action of a base to prepare a compound of formula II.
  • the base is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU) .
  • DBU 1, 8-Diazabicyclo [5.4.0] undec-7-ene
  • the equivalent of alkali is between 0.01 and 10.
  • the solvent is selected from one or more of water, methanol, ethanol, propanol, isopropanol, tert-butanol, n-butanol, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, toluene, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone.
  • the compound of formula I is reacted with compound A under the action of a base to prepare a compound of formula II, wherein the compound A is selected from L-2-aminobutanamide, L-2-aminobutanamide hydrochloride, L-2-aminobutyric acid or L-2-aminobutyric acid hydrochloride;
  • the base is selected from one or more of sodium methoxide, potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, Sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU) , and the equivalent of alkali is between 0.01 and 10;
  • the solvent is selected from
  • the compound of formula III-1 is prepared by reacting a compound of formula II in oxidation system in a solvent.
  • method for preparing compound of formula III-1 from compound of formula II wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO.
  • the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO.
  • the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) 2 /TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py ⁇ SO 3 ) , NaIO 4 /TEMPO/NaBr, NaIO 4 /TEMPO/KBr, KIO 4 /TEMPO/NaBr, KIO 4 /TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO 4 , NaMnO 4 , KMnO 4 /TEMPO or NaMnO 4 /TEMPO.
  • NMO/TPAP 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate
  • DMP Dess-Martin periodinane
  • the compound of formula III-1 is prepared by reacting a compound of formula II in oxidation system in a solvent, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO; the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) 2 /TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py ⁇ SO 3 ) , NaIO 4 /TEMPO/NaBr, NaIO 4 /TEMPO/KBr, KIO 4 /TEMPO
  • the solvent is selected
  • method for preparing compound of formula III-2 from compound of formula II wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO.
  • the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO.
  • the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) 2 /TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py ⁇ SO 3 ) , NaIO 4 /TEMPO/NaBr, NaIO 4 /TEMPO/KBr, KIO 4 /TEMPO/NaBr, KIO 4 /TEMPO/KBr, NaClO/TEMPO/NaBr or NaClO/TEMPO/KBr, KMnO 4 , NaMnO 4 , KMnO 4 /TEMPO or NaMnO 4 /TEMPO.
  • NMO/TPAP 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate
  • DMP Dess-Martin periodinane
  • the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H 2 , Pt/H 2 , Ni/H 2 , Pd (OH) 2 /H 2 or Pd/ammonium formate.
  • a product of a compound of formula II reacted with an oxidizing agent system is then reacted with a reducing agent to prepare a compound of formula III-2, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, n-butanol, acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran or DMF, N-methylpyrrolidone or DMSO; the oxidation system is selected from 4-Methylmorpholine N-oxide/Tetrapropylammonium perruthenate (NMO/TPAP) , DMSO/ (COCl) 2 /TEA, Dess-Martin periodinane (DMP) , DMSO/Sulfur trioxide pyridine complex (DMSO/Py ⁇ SO 3 ) , NaIO 4 /TEMPO/NaBr
  • the solvent is selected from one or more of
  • a compound of formula III-1-1 is used in a method of preparing Brivaracetam VI, which method comprises the steps of preparing formula VI by a compound of formula III-1-1:
  • preparation of the compound of formula IV-1 from the compound of formula III-1-1 removing the sulfonyl group on compound of formula III-1-1 by a reducing agent in an organic solvent to prepare a compound of formula IV-1.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 .
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in combination with one or more ofHg, I 2 , Lewis acid or base.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 , and is used in combination with one or more ofHg, I 2 , Lewis acid or base.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide,
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 , and is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bro
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in a molar equivalent of between 1 and 30;
  • the reducing agent is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 , and is used in a molar equivalent of between 1 and 30; the reducing agent is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenes
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is Mg, which is used in a molar equivalent of between 1 and 30, and the reducing agent is used in combination with one or more of hydrochloric acid, trimethyl chlorosilane, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate or potassium acetate.
  • a compound of formula IV-1 is reacted with a reducing agent in a solvent to prepare a compound of formula VI.
  • method for preparing compound of formula VI from compound of formula IV-1 wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, toluene, dichloromethane or tetrahydrofuran.
  • the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H 2 , Pt/H 2 , Ni/H 2 , Pd (OH) 2 /H 2 or Pd/ammonium formate.
  • a compound of formula IV-1 is reacted with a reducing agent in a solvent to prepare a compound of formula VI, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, acetonitrile, toluene, dichloromethane or tetrahydrofuran.
  • the reducing agent includes sodium borohydride, sodium cyanoborohydride, sodium triacetylborohydride, triethylsilane/trifluoroacetic acid, Pd/H 2 , Pt/H 2 , Ni/H 2 , Pd (OH) 2 /H 2 or Pd/ammonium formate.
  • a compound of formula III-1-1 is used in a method of preparing Brivaracetam VI, which method comprises the step of preparing formula VI by a compound of formula III-1-1:
  • a compound of formula III-2-1 is used in a method of preparing Brivaracetam VI, which method comprises the step of preparing formula VI by a compound of formula III-2-1:
  • the method for preparing Brivaracetam VI from compound of formula III-2-1 includes the step of removing the sulfonyl group on compound of formula III-2-1 by a reducing agent in an organic solvent.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 .
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in combination with one or more ofHg, I 2 , Lewis acid or base.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 , and is used in combination with one or more ofHg, I 2 , Lewis acid or base.
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bromide,
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 , and is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, citric acid, ammonia, methylmagnesium bro
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is selected from active metals and salts thereof, tin hydride or transition metals, and is used in a molar equivalent of between 1 and 30;
  • the reducing agent is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water; and the reducing agent is selected from Mg, Ca, Al, Zn, Ni, Sm, SmI 2 , and is used in a molar equivalent of between 1 and 30; the reducing agent is used in combination with one or more of Hg, I 2 , Lewis acid or base, wherein the Lewis acid and the Lewis base are selected from one or more of hydrochloric acid, ammonium chloride, trimethylchlorosilane, titanium tetrachloride, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenes
  • the organic solvent is selected from one or more of methanol, ethanol, isopropanol, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, or a mixed solvent with water;
  • the reducing agent is Mg, which is used in a molar equivalent of between 1 and 30, and the reducing agent is used in combination with one or more of hydrochloric acid, trimethyl chlorosilane, nickel chloride, nickel bromide, nickel iodide, acetic acid, propionic acid, methylmagnesium bromide, tetramethylethylenediamine, sodium acetate or potassium acetate.
  • the method for the preparation of Brivaracetam VI by using the compounds of formula III-1-2 includes the steps of preparing a compound of formula VI by a compound of formula III-1-2.
  • the method for the preparation of Brivaracetam VI by using the compounds of formula III-1-2 includes the steps of preparing a compound of formula VI by a compound of formula III-1-2.
  • the method for the preparation of Brivaracetam VI by using the compounds of formula III-2-2 includes the steps of preparing a compound of formula VI by a compound of formula III-2-2.
  • the method for the preparation of Brivaracetam VI by using the compounds of formula III-2-2 includes the steps of preparing a compound of formula VI by a compound of formula III-2-2.
  • the present invention has the following advantages over the prior art:
  • the present invention provides a method for preparing a compound of formula III, which is used to synthesize Brivaracetam APIs.
  • the synthetic route of this method is short, the raw materials are easy to obtain, the whole process is simple, and the operability is strong. It has potential industrial value and is suitable for industrial production.
  • C m -C n refers to the carbon atoms contained in m-n.
  • Alkyl refers to a saturated aliphatic hydrocarbon radical or linker including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • “Lower alkyl” refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include- (CH 2 ) 3 -, methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like. Alkyl may be substituted or unsubstituted.
  • Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and-NR x R y , where R x and R y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring.
  • Cycloalkyl refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares at least an adjacent carbon atom with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
  • cycloalkyl groups examples, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like.
  • a cycloalkyl group may be substituted or unsubstituted.
  • Typical substituent groups include alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, Camido, N-amido, nitro, amino and–NRxRy, with Rx and Ry as defined above.
  • Aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, Ocarbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and-NR x R y , with R x and R y as defined above.
  • Heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated ⁇ -electron system.
  • unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.
  • the heteroaryl group may be substituted or unsubstituted.
  • Typical substituents include alkyl, cycloalkyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and–NR x R y with R x and R y as defined above.
  • heteroalkyl include optionally substituted alkyl radicals in which one or more skeletal chain atoms is a heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof.
  • the heteroatom (s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 3 , -OCH 2 -, -CH 2 -NH-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -N (CH 3 ) -CH 3 , -NCH 2 CH 2 -, -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N (CH 3 ) -CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S (O) -CH 3 , -CH 2 -CH 2 -S (O) 2 -CH 3 .
  • up to two heteroatoms may be consecutive, such as, by way of example, -CH 2 -NH-OCH 3 .
  • Acyl or “carbonyl” refers to a -C (O) R" group, where R" is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and-NRxRy groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and-NRxRy groups and heteroalicyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and-NRxRy groups.
  • Alkoxy refers to both an -O- (alkyl) or an -O- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkyl or cycloalkyl group may be substituted or unsubstituted, and typical substituents include a halogen group and the like. Representative examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, and the like.
  • Aryloxy refers to an -O-aryl or an -O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • O-carboxy refers to a -OC (O) R" group, with R" as defined above.
  • Alcohol refers to a -C (O) CH 3 group.
  • Cyano refers to a -C ⁇ N group.
  • Niro refers to a -NO 2 group.
  • Aldehyde refers to an acyl group in which R" is hydrogen.
  • Hydrophilicity refers to an -OH group.
  • Halo group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • a “sulfonyl” group refers to a -S (O) 2 R" group wherein, in addition to being as defined above. Typical examples are methanesulfonyl (Ms) , benzenesulfonyl (Bs) , p-toluenesulfonyl (Ts) , and p-nitrobenzenesulfonyl (Ns) .
  • Ms methanesulfonyl
  • Bs benzenesulfonyl
  • Ts p-toluenesulfonyl
  • Ns p-nitrobenzenesulfonyl
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be different from the others.
  • optionally substituted or “substituted” means that the referenced group may be substituted with one or more additional group (s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • additional group individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsul
  • heterocycle group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycle group is substituted with an alkyl group and situations where the heterocycle group is not substituted with the alkyl group.
  • any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.
  • the compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers) , enantiomers or diastereomers.
  • any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • Compounds of Formula III include, but are not limited to optical isomers of compounds of Formula I, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • compounds of Formula III include Z- and E- forms (or cis- and trans- forms) of compounds with double bonds. Where compounds of Formula I exist in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.
  • the invention includes, but is not limited to, the following examples to further illustrate the preparation of the compounds described herein.
  • the chemical reagents used in the following examples are all commercially available chemical reagents.
  • Typical exemplary embodiments of the present invention are as follows:
  • Example 5 The synthesis of compounds II-1 ⁇ II-19 is similar to example 1
  • Example 11 The synthesis ofcompounds III-1-1 ⁇ III-1-19 is similar to example 6
  • Example 13 The synthesis ofcompounds III-1-1 ⁇ III-1-19 is similar to example 6

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé de formule III, ainsi que son utilisation et un procédé pour la synthèse de principes actifs pharmaceutiques brivaracétam. Les matières premières impliquées dans le procédé sont peu coûteuses et faciles à obtenir, et permettent de préparer des principes actifs pharmaceutiques brivaracétam de haute pureté optique, ce qui évite la séparation chirale et les étapes de séparation et de purification fastidieuses, réduit le coût et convient mieux pour une production industrielle.
PCT/CN2020/070948 2019-01-09 2020-01-08 Composés et leur utilisation dans la synthèse de principes actifs pharmaceutiques brivaracétam WO2020143674A1 (fr)

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